WO2007067027A1 - Pharmaceutical compositions containing combined antidiabetic substances for use in type 2 diabetes mellitus - Google Patents

Pharmaceutical compositions containing combined antidiabetic substances for use in type 2 diabetes mellitus Download PDF

Info

Publication number
WO2007067027A1
WO2007067027A1 PCT/MX2006/000060 MX2006000060W WO2007067027A1 WO 2007067027 A1 WO2007067027 A1 WO 2007067027A1 MX 2006000060 W MX2006000060 W MX 2006000060W WO 2007067027 A1 WO2007067027 A1 WO 2007067027A1
Authority
WO
WIPO (PCT)
Prior art keywords
accordance
pharmaceutical composition
pioglitazone
glimepiride
present
Prior art date
Application number
PCT/MX2006/000060
Other languages
Spanish (es)
French (fr)
Inventor
María Elena GARCÍA ARMENTA
Víctor Guillermo ÁLVAREZ OCHOA
Josefina Santos Murillo
Original Assignee
World-Trade Import-Export, Wtie, Ag.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by World-Trade Import-Export, Wtie, Ag. filed Critical World-Trade Import-Export, Wtie, Ag.
Priority to BRPI0619616-0A priority Critical patent/BRPI0619616A2/en
Priority to EP06769371A priority patent/EP1958636A1/en
Publication of WO2007067027A1 publication Critical patent/WO2007067027A1/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/64—Sulfonylureas, e.g. glibenclamide, tolbutamide, chlorpropamide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones

Definitions

  • the present invention describes a pharmaceutical composition that comprises a combination of antidiabetic substances such as a sulfonylurea such as Io is Glimepiride and a suitable thiazole such as Io is Pioglitazone for the pharmacological use of the composition in the treatment of Diabetes Mellitus type 2;
  • the composition produces a combination product with improved properties and produces a synergistic effect.
  • DM Diabetes mellitus
  • ICD International Classification of Diseases.
  • Diabetic retinopathy Diabetic retinopathy.
  • SULFONILUREAS All drugs in this group are derived from sulfa drugs, in which the sulfonylurea structure constitutes the essential group of hypoglycemic action. Sulfonylureas are known for their hypoglycemic activity, they are considered the drugs of choice in patients with type 2 DM of relatively recent onset ( ⁇ 5 years), who have endogenous insulin production, who are not obese and who do not respond adequately to treatment. dietary. Sulfonylureas stimulate beta cells in the pancreas to release more insulin. Sulfonylureas have been used since the 1950s. Chlorpropamide is the only first generation sulfonylurea that is still in use.
  • the second generation sulfonylureas are: Glipizida, Gliburida, Glimepirida. These medications are given once to twice a day before meals. All sulfonylureas produce similar effects on the level of glucose in the blood, but differ in side effects in the frequency with which they are administered and in the interactions with other medications.
  • Glimepiride decreases the concentration of glucose in the blood, by stimulating the release of insulin from the pancreatic beta cells, both in healthy subjects and in patients with type 2 diabetes II. This effect is mainly due to the fact that the response of the cells increases. pancreatic beta before the physiological stimulation of glucose.
  • Glimepiride is chemically Ia 1 - [[p- [2- (3- ethyl-4-methyl-2-oxo-3-pyrrolin-1-carboxamido) ethyl] phenyl] su Ifon il] -3- (trans-4 -methylcyclohexyl) urea. It has a molecular weight of 490.62; it is generally a crystalline white powder whose molecular structure is the following:
  • THIAZOLIDINEDIONAS OR GLITAZONES They are a new group of hypoglycemic agents, characterized by sensitizing or increasing the action of insulin without increasing its secretion, which is why they are useful in situations where peripheral resistance develops to insulin.
  • Thiazolidinediones work to improve insulin sensitivity in patients who have developed insulin resistance, reducing blood glucose, insulin and HbAIc levels, without causing hypoglycemia. They are indicated in patients with type 2 DM with insulin resistance or in patients who are poorly controlled with other forms of therapy. They can be used as monotherapy or in combination with insulin and other hypoglycemic drugs.
  • Pioglitazone is part of this group; decreases insulin resistance in the periphery and in the liver, and results in an increase in insulin-dependent glucose disposition, as well as a decrease in hepatic glucose expenditure. It helps insulin work better in muscle and fat and also reduces glucose production in the liver. Chemically it is [( ⁇ ) -5 - [[4- [2- (5-etii-2-pyridinyl) ethoxy] phenyl] methyl] -2,4-] thiazolidin-dion and is a white crystalline powder whose molecular structure is the following:
  • a pharmacological composition that comprises a combination of a sulfonylurea known as Glimepiride and a thiazolidinedione known as Pioglitazone, whose combination produces a synergistic effect on the hemoglobin and lucid ilates, with fewer ingredients, it is better tolerated and with less adverse effects in patients with type 2 diabetes Mellitus.
  • Glimepiride a sulfonylurea
  • Pioglitazone a thiazolidinedione
  • Glycated Hemoglobin decreased to 0.8% (95% Confidence Interval): 0.08% to 1.4% with the combination.
  • the group that received the combination had a percentage reduction in triglyceride levels of (25%, 95% CI, 15% to 34%) and an increase in high-density lipid levels (13%, CI, 8% 18%) compared to the group that received Glimepiride alone. In the combination group, there was no increase in low-density lipoprotein levels.
  • Group 1 reported no adverse events
  • group 2 reported 5 patients with adverse hypoglycemia events, who discontinued treatment and were reassigned to receive the combination, which was better tolerated without reporting adverse events.
  • the Glimepiride / Pioglitazone combination significantly improves glycated hemoglobin and plasma glucose levels with beneficial effects on cholesterol and triglyceride levels and without presenting adverse events.

Landscapes

  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Diabetes (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Endocrinology (AREA)
  • Epidemiology (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Emergency Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

The invention relates to a pharmaceutical composition which combines antidiabetic substances such as a sulphonylurea such as glimepiride and a thiazolidinedione such as pioglitazone and which is intended for pharmacological use in the treatment of type 2 diabetes mellitus. The aforementioned composition produces a combined product having improved properties, as well as producing a synergic effect. In summary, the invention comprises a synergic pharmaceutical composition containing a synergic combination of a sulphonylurea and a thiazolidinedione for the treatment of type 2 diabetes mellitus, in which the sulphonylurea is glimepiride and/or any of the salts thereof and the thiazolidinedione is pioglitazone and/or any of the salts thereof.

Description

COMPOSICIONES FARMACÉUTICAS QUE COMPRENDEN SUSTANCIAS ANTIDIABÉTICAS COMBINADAS PARA SU USO EN DIABETES MELLITUS TIPO 2  PHARMACEUTICAL COMPOSITIONS INCLUDING COMBINED ANTI-DIABETIC SUBSTANCES FOR USE IN TYPE 2 DIABETES MELLITUS
CAMPO DE LA INVENCIÓN FIELD OF THE INVENTION
La presente invención describe una composición farmacéutica que comprende una combinación de sustancias antidiabéticas como una sulfonilurea como Io es Ia Glimepirida y una tiazol id ined iona como Io es Ia Pioglitazona para el uso farmacológico de Ia composición en el tratamiento de Ia Diabetes Mellitus tipo 2; Ia composición produce un producto de combinación con propiedades mejoradas y produce un efecto sinérgico. The present invention describes a pharmaceutical composition that comprises a combination of antidiabetic substances such as a sulfonylurea such as Io is Glimepiride and a suitable thiazole such as Io is Pioglitazone for the pharmacological use of the composition in the treatment of Diabetes Mellitus type 2; The composition produces a combination product with improved properties and produces a synergistic effect.
ANTECEDENTES BACKGROUND
La diabetes mellitus (DM) es un importante problema de salud pú- blica en México. La tendencia al incremento se agudiza en 1998. En los últimos cinco años ha llegado a ocupar Ia primera causa de muerte con 11% del total de las defunciones en ambos sexos y 14% de las muertes son mujeres. De acuerdo a los datos de las estadísticas de diabetes en México, las causas de muerte son las com- plicaciones de Ia DM: COMPLICACIONES DE LADM CIE* Diabetes mellitus (DM) is a major public health problem in Mexico. The tendency to increase sharpened in 1998. In the last five years it has come to occupy the first cause of death with 11% of all deaths in both sexes and 14% of deaths are women. According to the data from diabetes statistics in Mexico, the causes of death are complications of DM: COMPLICATIONS OF LADM CIE *
1997 200' 1997 200 '
% % %%
Coma 3.9 4.5Eat 3.9 4.5
Cetoacidosis 5.2 3.2 Complicaciones renales 30.0 30.4 Complicaciones oftálmicas 0.0 0.0 Complicaciones neurológicas 0.3 0.2 Comp. de Ia circulación periférica 1.4 1.3 Otras complicaciones especificadas 20.7 17.6 Complicaciones múltiples 21.5 24.4 Complicaciones inespecíficas 2.8 3.6 Sin mención de complicaciones 14.1 14.9 Ketoacidosis 5.2 3.2 Renal complications 30.0 30.4 Ophthalmic complications 0.0 0.0 Neurological complications 0.3 0.2 Comp. of peripheral circulation 1.4 1.3 Other specified complications 20.7 17.6 Multiple complications 21.5 24.4 Nonspecific complications 2.8 3.6 No mention of complications 14.1 14.9
• CIE = Clasificación Internacional de Enfermedades. • ICD = International Classification of Diseases.
• Fuente CEMECE, 2002.  • Source CEMECE, 2002.
Es importante observar que las complicaciones renales de Ia DM son Ia mayor causa de muerte en estos pacientes, por esta razón Ia terapia de Ia DM debe estar enfocada al control de Ia glucosa y a Ia prevención de las complicaciones. It is important to note that renal complications of DM are the greatest cause of death in these patients, for this reason the therapy of DM must be focused on glucose control and the prevention of complications.
Las complicaciones crónicas ocurren después de haber tenido elevada Ia glucosa en sangre durante periodos prolongados (años) y son: Chronic complications occur after having high blood glucose for long periods (years) and are:
Retinopatía diabética. Diabetic retinopathy.
Nefropatía diabética. Diabetic kidney disease.
Neuropatía diabética. Diabetic neuropathy.
Complicaciones cardiovasculares. Como se menciona anteriormente los aspectos fundamentales en el tratamiento son: Ia dieta y control de peso, ejercicio, y terapia con medicamentos. Cardiovascular complications. As mentioned above, the fundamental aspects of treatment are: diet and weight control, exercise, and drug therapy.
Existen diferentes tipos de medicamentos utilizados en Ia terapia sin embargo, se ha observado que es mayormente efectiva Ia terapia combinada de medicamentos en esta patología en comparación a Ia monoterapia utilizada ya que con esta última no se ha encon- trado un efectivo control del índice glicémico. There are different types of drugs used in therapy, however, it has been observed that combined drug therapy is more effective in this pathology compared to the monotherapy used, since with the latter no effective control of the glycemic index has been found. .
Como se comentó, dentro de los medicamentos mayormente utilizados se encuentran varios sin embargo es de nuestro interés revisar las sulfonilureas y las tiazolidinedionas. As mentioned, several of the drugs are widely used, however it is in our interest to review the sulfonylureas and thiazolidinediones.
SULFONILUREAS: Todos los fármacos de este grupo son derivados de las sulfamidas, en los cuales Ia estructura sulfonilurea constituye el grupo esencial de Ia acción hipoglucemiante. Las sulfonilureas son conocidas por su actividad hipoglucemiante, se consideran los fármacos de elección en pacientes con DM tipo 2 de comienzo relativamente reciente (< 5 años), que tienen una producción endógena de insulina, que no sean obesos y que no respondan adecuadamente al tratamiento dietético. Las sulfonilureas estimulan a las células beta del páncreas para que liberen más insulina. Las sulfo- nilureas se utilizan desde Ia década de 1950. La clorpropamida es Ia única sulfonilurea de primera generación que aún se utiliza. Las sulfonilureas de segunda generación son: Glipizida, Gliburida, Glimepirida. Estos medicamentos se administran una a dos veces al día antes de las comidas. Todas las sulfonilureas producen efectos similares sobre el nivel de glucosa en Ia sangre, pero difieren en los efectos secundarios en Ia frecuencia con que se administran y en las interacciones con otros medicamentos. SULFONILUREAS: All drugs in this group are derived from sulfa drugs, in which the sulfonylurea structure constitutes the essential group of hypoglycemic action. Sulfonylureas are known for their hypoglycemic activity, they are considered the drugs of choice in patients with type 2 DM of relatively recent onset (<5 years), who have endogenous insulin production, who are not obese and who do not respond adequately to treatment. dietary. Sulfonylureas stimulate beta cells in the pancreas to release more insulin. Sulfonylureas have been used since the 1950s. Chlorpropamide is the only first generation sulfonylurea that is still in use. The second generation sulfonylureas are: Glipizida, Gliburida, Glimepirida. These medications are given once to twice a day before meals. All sulfonylureas produce similar effects on the level of glucose in the blood, but differ in side effects in the frequency with which they are administered and in the interactions with other medications.
La Glimepirida disminuye Ia concentración de glucosa en sangre, al estimular Ia liberación de insulina desde las células beta pancreáticas, tanto en sujetos sanos como en pacientes con diabetes MeIIi- tus tipo 2. Este efecto se debe principalmente a que aumenta Ia respuesta de las células beta pancreáticas ante el estímulo fisiológico de Ia glucosa. La Glimepirida es químicamente Ia 1-[[p-[2-(3- etil-4-metil-2-oxo-3-pirrolin-1-carboxamido) etil] Fenil] su Ifon i l]-3- (trans-4-metilciclohexil)urea. Tiene un peso molecular de 490.62; generalmente es un polvo blanco cristalino cuya estructura molecular es Ia siguiente:
Figure imgf000005_0001
Glimepiride decreases the concentration of glucose in the blood, by stimulating the release of insulin from the pancreatic beta cells, both in healthy subjects and in patients with type 2 diabetes II. This effect is mainly due to the fact that the response of the cells increases. pancreatic beta before the physiological stimulation of glucose. Glimepiride is chemically Ia 1 - [[p- [2- (3- ethyl-4-methyl-2-oxo-3-pyrrolin-1-carboxamido) ethyl] phenyl] su Ifon il] -3- (trans-4 -methylcyclohexyl) urea. It has a molecular weight of 490.62; it is generally a crystalline white powder whose molecular structure is the following:
Figure imgf000005_0001
TIAZOLIDINEDIONAS Ó GLITAZONAS: Son un nuevo grupo de hipo- glucemiantes, que se caracterizan por sensibilizar o incrementar Ia acción de Ia insulina sin que aumente su secreción, por Io que son útiles en situaciones en las que se desarrolla resistencia periférica a la insulina. Las tiazolidinedionas actúan mejorando Ia sensibilidad a la insulina en pacientes que han desarrollado resistencia a la insulina, disminuyendo los niveles de glucemia, de insulina y de HbAIc, sin llegar a producir hipoglucemia. Están indicadas en pacientes con DM tipo 2 con insulinorresistencia o en pacientes que están mal controlados con otras formas de terapia. Pueden emplearse en monoterapia o en asociación con insulina y otros hipo- glucemiantes. THIAZOLIDINEDIONAS OR GLITAZONES: They are a new group of hypoglycemic agents, characterized by sensitizing or increasing the action of insulin without increasing its secretion, which is why they are useful in situations where peripheral resistance develops to insulin. Thiazolidinediones work to improve insulin sensitivity in patients who have developed insulin resistance, reducing blood glucose, insulin and HbAIc levels, without causing hypoglycemia. They are indicated in patients with type 2 DM with insulin resistance or in patients who are poorly controlled with other forms of therapy. They can be used as monotherapy or in combination with insulin and other hypoglycemic drugs.
La Pioglitazona integra este grupo; disminuye Ia resistencia a Ia insulina en Ia periferia y en el hígado, y da como resultado un incremento en Ia disposición de glucosa insulino-dependiente, así como una disminución en el gasto de glucosa hepática. Ayuda a que Ia insulina funcione mejor en el músculo y Ia grasa y también, reduce Ia producción de glucosa en el hígado. Químicamente es el [(±)-5-[[4-[2-(5-etii-2-piridinil)etoxi]fenil]metil]-2,4-] tiazolidin-dion y es un polvo blanco cristalino cuya estructura molecular es Ia siguiente: Pioglitazone is part of this group; decreases insulin resistance in the periphery and in the liver, and results in an increase in insulin-dependent glucose disposition, as well as a decrease in hepatic glucose expenditure. It helps insulin work better in muscle and fat and also reduces glucose production in the liver. Chemically it is [(±) -5 - [[4- [2- (5-etii-2-pyridinyl) ethoxy] phenyl] methyl] -2,4-] thiazolidin-dion and is a white crystalline powder whose molecular structure is the following:
7.1
Figure imgf000006_0001
7.1
Figure imgf000006_0001
Fisiopatología de Diabetes tipo 2: Pathophysiology of Type 2 Diabetes:
La mayoría de estudios longitudinales han mostrado claramente que la resistencia a Ia insulina es el mayor factor de riesgo para el de- sarro lio de diabetes tipo 2. En un estudio prospectivo de Pima In- dians, Lillioja et al evaluó el papel relativo de Ia obesidad, resistencia a Ia insulina y Ia disfunción de las células β en el desarrollo de diabetes mellitus tipo 2 en sujetos con tolerancia a Ia glucosa normal o insuficiente tolerancia a Ia glucosa. Concluyeron que Ia resistencia a Ia insulina fue un factor mayor de riesgo para el desarrollo de diabetes, con secreción de insulina siendo un factor de riesgo adicional pero débil. El argumento más importante que soporta Ia resistencia a Ia insulina como el mayor factor genético primario que lleva a Ia diabetes son las observaciones en donde aparece que este problema precede a Ia insuficiente función de las células β. Most longitudinal studies have clearly shown that insulin resistance is the greatest risk factor for de tartar of type 2 diabetes. In a prospective study by Pima Indians, Lillioja et al evaluated the relative role of obesity, insulin resistance and β-cell dysfunction in the development of type 2 diabetes mellitus in subjects with tolerance to normal glucose or insufficient tolerance to glucose. They concluded that insulin resistance was a major risk factor for the development of diabetes, with insulin secretion being an additional but weak risk factor. The most important argument supporting insulin resistance as the largest primary genetic factor leading to diabetes are the observations where it appears that this problem precedes the insufficient function of β cells.
Para resumir, Ia resistencia a Ia insulina parece explicarse mayor- mente por Ia presencia de obesidad. De hecho, Ia reducción de peso está asociada con una normalización de Ia sensibilidad a Ia insulina. Por otro lado, Ia disfunción que está presente años antes que aparezca Ia intolerancia a Ia glucosa y ninguna intervención está disponible para corregir esta anormalidad. Esto pudiera sopor- tar el concepto de que Ia insuficiencia de las células β es el defecto primario que lleva al desarrollo de diabetes. La resistencia a Ia insulina adquirida por Ia obesidad y Ia disminución de Ia actividad física aceleran Ia progresión a Ia diabetes. Esto pudiera explicar Ia explosión epidémica de diabetes en un mundo con alimentos grasos y más sedentarismo. Por Io tanto los tratamientos iniciales se enfocan a Ia reducción de peso, ejercicio y dieta así como tratamiento farmacológico. To summarize, insulin resistance seems to be explained mainly by the presence of obesity. In fact, weight reduction is associated with a normalization of insulin sensitivity. On the other hand, the dysfunction that is present years before glucose intolerance appears and no intervention is available to correct this abnormality. This could support the concept that the failure of β cells is the primary defect that leads to the development of diabetes. The resistance to insulin acquired by obesity and the decrease in physical activity accelerate the progression to diabetes. This could explain the epidemic explosion of diabetes in a world with fatty foods and more sedentary lifestyle. For this reason, both initial treatments focus on weight reduction, exercise and diet, as well as treatment pharmacological.
Una basta mayoría de pacientes que utilizan combinaciones de medicamentos aunado a dietas y ejercicio han reportado eventos ad- versos; entre los mas comunes se encuentra, Ia hipoglicemia severa, que incluye temblor fino, sudoración, nausea y vómito que puede llegar a ser grave; esto es debido a las interacciones de los fármacos ya que algunas combinaciones potencian el efecto hipo- glucemiante. Por esta razón realizamos pruebas con nuestra combi- nación con el objetivo de evaluar Ia sinergia de ambos compuestos, Ia eficacia sobre los índices glicémicos; así como su tolerancia evaluando los efectos adversos, utilizando menores dosis de los ingredientes. A vast majority of patients using combinations of medications in combination with diet and exercise have reported adverse events; Among the most common are: severe hypoglycemia, which includes fine tremor, sweating, nausea, and vomiting that can be severe; this is due to drug interactions and some combinations enhance the hypoglycemic effect. For this reason, we carried out tests with our combination with the objective of evaluating the synergy of both compounds, the efficacy on glycemic indexes; as well as its tolerance evaluating the adverse effects, using lower doses of the ingredients.
DESCRIPCIÓN DETALLADA DEL INVENTO DETAILED DESCRIPTION OF THE INVENTION
De acuerdo a Ia presente invención, realizamos una composición farmacológica que comprende una combinación de una sulfonilurea conocida como Glimepirida y una tiazolidinediona conocida como Pioglitazona cuya combinación produce un efecto sinérgico en los índices de hemoglobina g lucos ilada, con menor cantidad de ingredientes, es mejor tolerada y con menores efectos adversos en pacientes con diabetes Mellitus tipo 2. EJEMPLO 1: According to the present invention, we carry out a pharmacological composition that comprises a combination of a sulfonylurea known as Glimepiride and a thiazolidinedione known as Pioglitazone, whose combination produces a synergistic effect on the hemoglobin and lucid ilates, with fewer ingredients, it is better tolerated and with less adverse effects in patients with type 2 diabetes Mellitus. EXAMPLE 1:
Realizamos un estudio comparativo para evaluar Ia eficacia y tolerancia de una combinación de sulfonilurea con una tiazolidinediona como fueron Glimepirida / Pioglitazona comparado a Ia administra- ción de una tiazolidinediona Ia Pioglitazona sola, en el tratamiento de pacientes con diabetes Mellitus tipo 2. El estudio fue de 16 semanas, doble ciego, que incluyó 20 pacientes con diagnóstico de diabetes Mellitus tipo 2, con una hemoglobina glucosilada > ó = 8.0%, con elevación de los niveles de triglicéridos; los pacientes fueron randomizados para recibir el Grupo 1 (n = 10) Ia combinación una vez al día, el Grupo 2 (n = 10) se asignó para recibir Pioglitazona sola dos veces al día.  We carried out a comparative study to evaluate the efficacy and tolerance of a combination of sulfonylurea with a thiazolidinedione such as Glimepiride / Pioglitazone compared to the administration of a thiazolidinedione Pioglitazone alone, in the treatment of patients with type 2 diabetes Mellitus. The study was 16-week, double-blind, which included 20 patients diagnosed with type 2 diabetes Mellitus, with a glycosylated hemoglobin> or = 8.0%, with elevated triglyceride levels; patients were randomized to receive Group 1 (n = 10) the combination once a day, Group 2 (n = 10) was assigned to receive Pioglitazone alone twice a day.
Resultados: Results:
Los pacientes que recibieron Ia combinación de Glimepirida / Pio- glitazona tuvieron una disminución significativa de los niveles básales (P = <0.05) en Ia Hemoglobina glucosilada comparado al grupo de Pioglitazona sola. La Hemoglobina glucosilada disminuyó a 0.9% (95% de Intervalo de Confianza): 0.06% a 1.2% con Ia combinación. El grupo que recibió Ia combinación tuvo un porcentaje de reduc- ción de los niveles de triglicéridos de (26%, 95% IC, 16% a 36%) y un incremento en los niveles de lípidos de alta densidad (13%, IC, 8% a 18%) comparado con el grupo que recibió Pioglitazona sola. En el grupo de Ia . combinación hubo un pequeño incremento pero significativo de los niveles de lipoproteínas de baja densidad. El grupo 1 no reportó eventos adversos, el grupo 2 reportó 3 pacientes con hipoglucemia que no fue severa y que cedió con Ia adminis- tración de miel. No hubo necesidad de suspenderlos del estudio. Patients who received the combination of Glimepiride / Pioglitazone had a significant decrease in basal levels (P = <0.05) in glycated hemoglobin compared to the Pioglitazone group alone. Glycated hemoglobin decreased to 0.9% (95% Confidence Interval): 0.06% to 1.2% with the combination. The group that received the combination had a percentage reduction in triglyceride levels of (26%, 95% CI, 16% to 36%) and an increase in high-density lipid levels (13%, CI, 8% to 18%) compared to the group that received Pioglitazone alone. In Ia's group. combination there was a small but significant increase in low-density lipoprotein levels. Group 1 reported no adverse events, group 2 reported 3 patients with hypoglycaemia that was not severe and that gave with the administration tration of honey. There was no need to suspend them from the study.
Conclusiones: En pacientes con diabetes Mellitus tipo 2 Ia combinación de Glimepirida / Pioglitazona mejora significativamente Ia Hemoglobina glucosilada y los niveles plasmáticos de glucosa con efectos benéficos sobre los niveles de colesterol y triglicéridos, sin eventos adversos. Conclusions: In patients with type 2 diabetes Mellitus the combination of Glimepiride / Pioglitazone significantly improves glycated hemoglobin and plasma glucose levels with beneficial effects on cholesterol and triglyceride levels, without adverse events.
EJEMPLO 2: EXAMPLE 2:
Realizamos un estudio comparativo para evaluar Ia eficacia y tolerancia de una combinación de sulfonilurea con una tiazolidinediona como fueron Glimepirida / Pioglitazona comparado a Ia administración de una sulfonilurea Ia Glimepirida sola, en el tratamiento de pacientes con diabetes Mellitus tipo 2. El estudio fue de 16 sema- ñas, doble ciego, que incluyó 20 pacientes con diagnóstico de diabetes Mellitus tipo 2, con una hemoglobina glucosilada > ó = 8.0%, con elevación de los niveles de triglicéridos; los pacientes fueron randomizados para recibir el Grupo 1 (n = 10) Ia combinación una vez al día, el Grupo 2 (n= 10) se asignó para recibir Glimepirida dos veces al día. We carried out a comparative study to evaluate the efficacy and tolerance of a combination of sulfonylurea with a thiazolidinedione such as Glimepiride / Pioglitazone compared to the administration of a sulfonylurea Glimepiride alone, in the treatment of patients with type 2 diabetes Mellitus. The study was 16 weeks, double-blind, which included 20 patients diagnosed with type 2 diabetes Mellitus, with a glycated hemoglobin> or = 8.0%, with elevated triglyceride levels; patients were randomized to receive Group 1 (n = 10) the combination once a day, Group 2 (n = 10) was assigned to receive Glimepiride twice a day.
Resultados: Results:
Los pacientes que recibieron Ia combinación de Glimepirida / Pioglitazona tuvieron una disminución significativa de los niveles ba- sales (P = <0.05) en Ia Hemoglobina glucosilada comparado al grupo de Glimepirida sola. La Hemoglobina glucosilada disminuyó a 0.8% (95% de Intervalo de Confianza): 0.08% a 1.4% con Ia combinación. El grupo que recibió Ia combinación tuvo un porcentaje de reducción de los niveles de triglicéridos de (25%, 95% IC, 15% a 34%) y un incremento en los niveles de lípidos de alta densidad (13%, IC, 8% a 18%) comparado con el grupo que recibió Glimepirida sola. En el grupo de Ia combinación no hubo incremento de los niveles de lipoproteínas de baja densidad. El grupo 1 no reportó eventos adversos, el grupo 2 reportó 5 pacientes con eventos adversos de hi- poglicemia, los cuales suspendieron el tratamiento y fueron reasig- nados para recibir Ia combinación, Io cual fue mejor tolerado sin reportar eventos adversos. The patients who received the Glimepiride / Pioglitazone combination had a significant decrease in the basal levels (P = <0.05) in glycated hemoglobin compared to the Glimepiride group alone. Glycated Hemoglobin decreased to 0.8% (95% Confidence Interval): 0.08% to 1.4% with the combination. The group that received the combination had a percentage reduction in triglyceride levels of (25%, 95% CI, 15% to 34%) and an increase in high-density lipid levels (13%, CI, 8% 18%) compared to the group that received Glimepiride alone. In the combination group, there was no increase in low-density lipoprotein levels. Group 1 reported no adverse events, group 2 reported 5 patients with adverse hypoglycemia events, who discontinued treatment and were reassigned to receive the combination, which was better tolerated without reporting adverse events.
Conclusiones: Conclusions:
En pacientes con diabetes Mellitus tipo 2 Ia combinación de Glimepirida / Pioglitazona mejora significativamente Ia Hemoglobina glu- cosilada y los niveles plasmáticos de glucosa con efectos benéficos sobre los niveles de colesterol y triglicéridos y sin presentar eventos adversos. In patients with type 2 diabetes Mellitus, the Glimepiride / Pioglitazone combination significantly improves glycated hemoglobin and plasma glucose levels with beneficial effects on cholesterol and triglyceride levels and without presenting adverse events.
NOVEDAD DE LA INVENCIÓN NOVELTY OF THE INVENTION
Habiendo descrito Ia presente invención, se considera como nove- dad y, por Io tanto, se relaciona como propiedad Io contenido en las siguientes reivindicaciones: Having described the present invention, it is considered as a novelty and, therefore, is related to the property contained in the following claims:

Claims

REIVINDICACIONES
1.- Composición farmacéutica sinérgica que comprende una combi- nación sinérgica de una sulfonilurea y una tiazol ¡din edion a para el tratamiento de Ia Diabetes Mellitus tipo 2. 1.- Synergistic pharmaceutical composition comprising a synergistic combination of a sulphonylurea and a thiazoleidene for the treatment of Type 2 Diabetes Mellitus.
2. Composición farmacéutica en conformidad con Ia reivindicación 1 caracterizada porque comprende Ia combinación sinérgica, en Ia cuál Ia sulfonilurea es Ia Glimepirida y/o cualquiera de sus sales y Ia T i a z o I i d i n e d i o n a es Ia Pioglitazona y/o cualquiera de sus sales. 2. Pharmaceutical composition in accordance with claim 1 characterized in that it comprises the synergistic combination, in which the sulfonylurea is Glimepiride and / or any of its salts and the T i a z or I i d i n e d i or n a is the Pioglitazone and / or any of its salts.
3. Una composición farmacéutica en conformidad con Ia reivindicación 2 caracterizada además porque su combinación de ingredien- tes mejora significativamente los niveles plasmáticos de glucosa con efectos benéficos sobre los niveles de colesterol y triglicéri- dos, sin eventos adversos. 3. A pharmaceutical composition in accordance with claim 2, further characterized in that its combination of ingredients significantly improves plasma glucose levels with beneficial effects on cholesterol and triglyceride levels, without adverse events.
4. Una composición farmacéutica en conformidad con Ia reivindica- ción 3 caracterizada porque Ia Pioglitazona se encuentra como clorhidrato de Pioglitazona. 4. A pharmaceutical composition in accordance with claim 3 characterized in that Pioglitazone is found as Pioglitazone hydrochloride.
5. Una composición farmacéutica en conformidad con Ia reivindicación 2 caracterizada porque Ia Pioglitazona se encuentra presente en un rango de 5 mg a 35 mg por unidad de dosificación. 5. A pharmaceutical composition in accordance with claim 2 characterized in that Pioglitazone is present in a range of 5 mg to 35 mg per dosage unit.
6. Una composición farmacéutica en conformidad con Ia reivindica- ción 5 caracterizada porque Ia Pioglitazona se encuentra presente en una concentración de 15 mg por unidad de dosificación. 6. A pharmaceutical composition in accordance with claim- tion 5 characterized in that Pioglitazone is present in a concentration of 15 mg per dosage unit.
7. Una composición farmacéutica en conformidad con Ia reivindica- ción 7 caracterizada porque Ia Pioglitazona se encuentra presente en una concentración de 30 mg por unidad de dosificación. 7. A pharmaceutical composition in accordance with claim 7 characterized in that Pioglitazone is present in a concentration of 30 mg per dosage unit.
8. Una composición farmacéutica en conformidad con Ia reivindicación 2 caracterizada porque Ia Glimepirida se encuentra presente en una concentración menor de 6 mg de Glimepirida por unidad de dosificación. 8. A pharmaceutical composition in accordance with claim 2 characterized in that Glimepiride is present in a concentration of less than 6 mg of Glimepiride per dosage unit.
9. Una composición farmacéutica en conformidad con Ia reivindicación 10 en Ia cuál Ia Glimepirida se encuentra presente en una con- centración de 2 mg por unidad de dosificación. 9. A pharmaceutical composition in accordance with claim 10 in which Glimepiride is present in a concentration of 2 mg per dosage unit.
10. Una composición farmacéutica en conformidad con Ia reivindicación 10 en Ia cuál Ia Glimepirida se encuentra presente en una concentración de 4 mg por unidad de dosificación. 10. A pharmaceutical composition in accordance with claim 10 in which Glimepiride is present in a concentration of 4 mg per dosage unit.
11. Una composición farmacéutica en conformidad con Ia reivindicación 2 en Ia cuál Ia Pioglitazona se encuentra presente en un porcentaje del 2.7% al 19%, preferentemente del 8% al 16%. 11. A pharmaceutical composition in accordance with claim 2 in which the Pioglitazone is present in a percentage of 2.7% to 19%, preferably from 8% to 16%.
12. Una composición farmacéutica en conformidad con Ia reivindicación 13 en Ia cuál el porcentaje de Pioglitazona es del 16%. 12. A pharmaceutical composition in accordance with claim 13 in which the percentage of Pioglitazone is 16%.
13. Una composición farmacéutica en conformidad con la reivindicación 13 en Ia cuál el porcentaje de Pioglitazona es del 8%. 13. A pharmaceutical composition according to claim 13 in which the percentage of Pioglitazone is 8%.
14. Una composición farmacéutica en conformidad con Ia reivindicación 2 en Ia cuál Ia Glimepirida se encuentra presente en un porcentaje del 0.5% al 3%, preferentemente del 1% al 2.5%. 14. A pharmaceutical composition in accordance with claim 2 in which Glimepiride is present in a percentage of 0.5% to 3%, preferably 1% to 2.5%.
15. Una composición farmacéutica en conformidad con Ia reivindi- cación 16 en Ia cuál el porcentaje de Glimepirida es del 1.11%. 15. A pharmaceutical composition in accordance with claim 16 in which the percentage of Glimepiride is 1.11%.
16. Una composición farmacéutica en conformidad con Ia reivindicación 16 en Ia cuál el porcentaje de Glimepirida es del 2.22%. 16. A pharmaceutical composition in accordance with claim 16 in which the percentage of Glimepiride is 2.22%.
17. Composiciones farmacéuticas en conformidad con todas las reivindicaciones anteriores caracterizada porque se excluyen de Ia formulación sustancias inhibidoras de Ia HMG-CoA reductasa tales como Ia Pravastatina, Cerivastatina, Nivastatina, Vibastatina, Lo- vastatina, Simustatina, Fluvastatina, Rivastatina y Atorvastatina. 17. Pharmaceutical compositions in accordance with all the preceding claims, characterized in that HMG-CoA reductase inhibiting substances such as Pravastatin, Cerivastatin, Nivastatin, Vibastatin, Lovastatin, Simustatin, Fluvastatin, Rivastatin and Atorvastatin are excluded from the formulation.
18. Composiciones farmacéuticas en conformidad con todas las reivindicaciones anteriores caracterizada porque de tratarse de tabletas recubiertas, Ia Pioglitazona no forma parte del recubrimiento de Ia misma. 18. Pharmaceutical compositions in accordance with all the preceding claims, characterized in that being treated with coated tablets, Pioglitazone does not form part of the coating thereof.
19. Composiciones farmacéuticas en conformidad con todas las reivindicaciones anteriores caracterizada porque se excluyen de Ia formulación Biguanidas tales como Ia Metformina, Buformlna o Fen- formina. 19. Pharmaceutical compositions in accordance with all the preceding claims characterized in that they are excluded from Ia Biguanide formulation such as Metformin, Buformin or Phenformin.
20. Composiciones farmacéuticas en conformidad con todas las rei- vindicaciones anteriores caracterizada porque se excluyen de Ia formulación sustancias tales como el Fenofibrato, Gemfibrozil, CIo- fibrato, Clorpropamida, Glicazída, Acarbosa, miglitol, Insulina e 1 m pl itapid a . 20. Pharmaceutical compositions in accordance with all the preceding claims, characterized in that substances such as Fenofibrate, Gemfibrozil, CI-fibrate, Chlorpropamide, Glicazida, Acarbose, miglitol, Insulin and 1 m pl itapid a are excluded from the formulation.
21. Una composición farmacéutica en conformidad con todas las reivindicaciones anteriores caracterizada porque se excluye de la misma Ia mezcla con algún agente hipolipidémico y/o agente para el tratamiento de Ia obesidad. 21. A pharmaceutical composition in accordance with all the preceding claims characterized in that the mixture with some hypolipidemic agent and / or agent for the treatment of obesity is excluded.
22. El uso de las composiciones de conformidad con la reivindicación 2, para el tratamiento de Ia diabetes mellitus tipo 2. 22. The use of the compositions according to claim 2, for the treatment of type 2 diabetes mellitus.
PCT/MX2006/000060 2005-12-06 2006-06-23 Pharmaceutical compositions containing combined antidiabetic substances for use in type 2 diabetes mellitus WO2007067027A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
BRPI0619616-0A BRPI0619616A2 (en) 2005-12-06 2006-06-23 pharmaceutical compositions comprising combined antidiabetic substances for their use in type 2 diabetes mellitus
EP06769371A EP1958636A1 (en) 2005-12-06 2006-06-23 Pharmaceutical compositions containing combined antidiabetic substances for use in type 2 diabetes mellitus

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
MXPA/A/2005/013220 2005-12-06
MXPA05013220A MXPA05013220A (en) 2005-12-06 2005-12-06 Pharmaceutical compositions comprising combined antidiabetic substances for treating diabetes mellitus type 2.

Publications (1)

Publication Number Publication Date
WO2007067027A1 true WO2007067027A1 (en) 2007-06-14

Family

ID=38123117

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/MX2006/000060 WO2007067027A1 (en) 2005-12-06 2006-06-23 Pharmaceutical compositions containing combined antidiabetic substances for use in type 2 diabetes mellitus

Country Status (6)

Country Link
EP (1) EP1958636A1 (en)
BR (1) BRPI0619616A2 (en)
CR (1) CR10053A (en)
EC (1) ECSP088507A (en)
MX (1) MXPA05013220A (en)
WO (1) WO2007067027A1 (en)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5859037A (en) * 1997-02-19 1999-01-12 Warner-Lambert Company Sulfonylurea-glitazone combinations for diabetes
US6303640B1 (en) * 1995-06-20 2001-10-16 Takeda Chemical Industries, Ltd. Pharmaceutical composition
US20040147564A1 (en) * 2003-01-29 2004-07-29 Rao Vinay U. Combinations of glimepiride and the thiazolidinedione for treatment of diabetes
WO2005041962A1 (en) * 2003-10-31 2005-05-12 Takeda Pharmaceutical Company Limited Solid preparation comprising an insulin sensitizer, an insulin secretagogue and a polyoxyethylene sorbitan fatty acid ester

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6303640B1 (en) * 1995-06-20 2001-10-16 Takeda Chemical Industries, Ltd. Pharmaceutical composition
US5859037A (en) * 1997-02-19 1999-01-12 Warner-Lambert Company Sulfonylurea-glitazone combinations for diabetes
US20040147564A1 (en) * 2003-01-29 2004-07-29 Rao Vinay U. Combinations of glimepiride and the thiazolidinedione for treatment of diabetes
WO2005041962A1 (en) * 2003-10-31 2005-05-12 Takeda Pharmaceutical Company Limited Solid preparation comprising an insulin sensitizer, an insulin secretagogue and a polyoxyethylene sorbitan fatty acid ester

Also Published As

Publication number Publication date
ECSP088507A (en) 2008-07-30
MXPA05013220A (en) 2007-06-05
CR10053A (en) 2008-08-06
EP1958636A1 (en) 2008-08-20
BRPI0619616A2 (en) 2011-10-04

Similar Documents

Publication Publication Date Title
US11026901B2 (en) Treatment or prevention of cardiovascular events via the administration of a colchicine derivative
ES2302702T3 (en) PHARMACEUTICAL COMPOSITION THAT INCLUDES A COMBINATION OF METFORMIN AND GLIBENCLAMIDE.
EP3791872A1 (en) Methods of preventing cardiovascular events in residual risk dyslipidemic populations
KR100873585B1 (en) Drugs for complications of diabetes
US20150057306A1 (en) Compositions comprising scopolamine and ketamine in the treatment of depression
JP2007528886A (en) Use of metformin and orlistat for the treatment or prevention of obesity
Lau Diabetes and weight management
KR20120016051A (en) Pharmaceutical compositions
Abbatecola et al. Antidiabetic oral treatment in older people: does frailty matter?
WO2008111956A2 (en) Fatty acid oxidation inhibitors treating hyperglycemia and related disorders
WO2003061643A1 (en) Pharmaceutical composition that is used to control blood glucose in patients with type 2 diabetes
Schechter et al. Management of severe insulin resistance in patients with type 1 diabetes
JP2018199692A (en) Methods and compositions for treatment of diabetes and related symptoms
JP2010522762A (en) Method for the treatment of diabetes and composition of probucol derivatives
WO2014008374A2 (en) Combination therapies comprising metformin salts and antihyperglycemia agents or antihyperlipidemia agents
AU2011257964B2 (en) Anti-diabetic compositions and methods
US20060275249A1 (en) Co-therapy for diabetic conditions
WO2007067027A1 (en) Pharmaceutical compositions containing combined antidiabetic substances for use in type 2 diabetes mellitus
Guillausseau PROactive study
ES2359910T3 (en) MEDICINAL COMPOSITION TO INHIBIT THE EXPRESSION OF ATP-CITRATE LIASA AND ITS USE.
WO2010028211A1 (en) Health care
Goldstein PROactive study
JP2007091641A (en) Combinational pharmaceutical for treating type-ii diabetes
Morris Building therapy in type 2 diabetes–metformin and beyond
KR20220157906A (en) Pharmaceutical composition for preventing or treating diabetes mellitus in canine animals containing enavogliflozin

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 08057805

Country of ref document: CO

Ref document number: 2006769371

Country of ref document: EP

Ref document number: CR2008-010053

Country of ref document: CR

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: PI0619616

Country of ref document: BR

Kind code of ref document: A2

Effective date: 20080606